{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T10:06:37Z","timestamp":1784541997647,"version":"3.55.0"},"reference-count":23,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T00:00:00Z","timestamp":1784332800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The rapid emergence of carbapenem-resistant Acinetobacter baumannii has become a major health concern, primarily driven by the dissemination of class D \u03b2-lactamases, particularly OXA-23, which compromise the efficacy of last-line \u03b2-lactam antibiotics. Drug repurposing combined with structure-based computational approaches provides a promising strategy for accelerating the discovery of novel therapeutic candidates against multidrug-resistant pathogens. This study aimed to identify FDA-approved non-steroidal anti-inflammatory drugs (NSAIDS) with potential inhibitory activity against OXA-23 \u03b2-lactamase by using a comprehensive computational drug discovery workflow. Twenty-six FDA-approved NSAIDs were evaluated using an integrated computational pipeline comprising network pharmacology, KEGG pathway analysis, molecular docking, molecular dynamics simulations and ADMET profiling. KEGG pathway analysis confirmed the central role of OXA-23 in \u03b2-lactam resistance, while network pharmacology prioritized nine candidates NSAIDS for subsequent structure-based investigation. Molecular docking was performed using the crystal structure of OXA-23 \u03b2-lactamase (PDB ID: 4K0X), followed by molecular dynamics simulations to assess the stability of the protein\u2013ligand complexes. Among the prioritized compounds, sulfasalazine demonstrated the most favorable predicted binding affinity (\u22128.3 kcal\/mol), forming stable interactions with key catalytic residues, including SER126, VAL128, and LEU166 and exhibiting a more favorable docking profile than the reference drug imipenem (\u22125.7 kcal\/mol). Molecular dynamics simulations supported the structural stability of the sulfasalazine OXA-23 complex throughout the simulation period. Furthermore, ADMET analysis indicated favorable pharmacokinetic characteristics including good oral bioavailability, high gastrointestinal absorption, low central nervous system penetration, and an acceptable predicted safety profile. This integrated computational study identifies sulfasalazine as a promising repurposing candidate for targeting OXA-23 \u03b2-lactamase in carbapenem-resistant A. baumannii. The findings demonstrate the utility of combining network pharmacology with molecular modeling to prioritize candidate therapeutics and provide a computational framework for accelerating antimicrobial drug discovery. Experimental validation is warranted to confirm the inhibitory activity and therapeutic potential of sulfasalazine against multidrug-resistant A. baumannii.<\/jats:p>","DOI":"10.3390\/ijms27146390","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T09:32:54Z","timestamp":1784539974000},"page":"6390","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Network Pharmacology Guided Drug Repurposing and Molecular Modeling Identify Sulfasalazine as a Potential OXA-23 \u03b2-Lactamase in Carbapenem-Resistant Acinetobacter baumannii"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2613-7553","authenticated-orcid":false,"given":"Hanan Abdulrahman","family":"Sagini","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, College of Sciences, University of Jeddah, Jeddah 21959, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"243","DOI":"10.4161\/viru.19700","article-title":"Acinetobacter baumannii: An emerging opportunistic pathogen","volume":"3","author":"Howard","year":"2012","journal-title":"Virulence"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Ayoub Moubareck, C., and Hammoudi Halat, D. (2020). Insights into Acinetobacter baumannii: A Review of Microbiological, Virulence, and Resistance Traits in a Threatening Nosocomial Pathogen. Antibiotics, 9.","DOI":"10.3390\/antibiotics9030119"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Yehya, A., Ezzeddine, Z., Chakkour, M., Dhaini, Z., Bou Saba, M.S., Bou Saba, A.S., Nohra, L., Nassar, N.B., Yassine, M., and Bahmad, H.F. (2025). The intricacies of Acinetobacter baumannii: A multifaceted comprehensive review of a multidrug-resistant pathogen and its clinical significance and implications. Front. Microbiol., 16.","DOI":"10.3389\/fmicb.2025.1565965"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.2147\/IDR.S166750","article-title":"Insight into Acinetobacter baumannii: Pathogenesis, global resistance, mechanisms of resistance, treatment options, and alternative modalities","volume":"11","author":"Asif","year":"2018","journal-title":"Infect. Drug Resist."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"111367","DOI":"10.1016\/j.isci.2024.111367","article-title":"Carbapenem-resistant Acinetobacter baumannii raises global alarm for new antibiotic regimens","volume":"27","author":"Thacharodi","year":"2024","journal-title":"iScience"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"69","DOI":"10.4103\/ijabmr.ijabmr_49_25","article-title":"Genetically Divert Carbapenemase-resistant Acinetobacter baumannii: Better to be Safe than Sorry","volume":"15","author":"Das","year":"2025","journal-title":"Int. J. Appl. Basic Med. Res."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Scoffone, V.C., Trespidi, G., Barbieri, G., Arshad, A., Israyilova, A., and Buroni, S. (2025). The Evolution of Antimicrobial Resistance in Acinetobacter baumannii and New Strategies to Fight It. Antibiotics, 14.","DOI":"10.3390\/antibiotics14010085"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Thirapanmethee, K., Srisiri-A-Nun, T., Houngsaitong, J., Montakantikul, P., Khuntayaporn, P., and Chomnawang, M.T. (2020). Prevalence of OXA-Type \u03b2-Lactamase Genes among Carbapenem-Resistant Acinetobacter baumannii Clinical Isolates in Thailand. Antibiotics, 9.","DOI":"10.3390\/antibiotics9120864"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Kyriakidis, I., Vasileiou, E., Pana, Z.D., and Tragiannidis, A. (2021). Acinetobacter baumannii Antibiotic Resistance Mechanisms. Pathogens, 10.","DOI":"10.3390\/pathogens10030373"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"821","DOI":"10.3855\/jidc.15902","article-title":"The susceptibility pattern and distribution of blaOXA-23 genes of clinical isolate Acinetobacter baumannii in a tertiary hospital, Indonesia","volume":"16","author":"Anggraini","year":"2022","journal-title":"J. Infect. Dev. Ctries."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s40265-024-02104-6","article-title":"Treatment Approaches for Carbapenem-Resistant Acinetobacter baumannii Infections","volume":"85","author":"Iovleva","year":"2025","journal-title":"Drugs"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1134\/S1068162023020139","article-title":"Drug Repurposing: An Effective Tool in Modern Drug Discovery","volume":"49","author":"Kulkarni","year":"2023","journal-title":"Russ. J. Bioorg. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Le\u00e3o, C., Borges, A., and Sim\u00f5es, M. (2020). NSAIDs as a Drug Repurposing Strategy for Biofilm Control. Antibiotics, 9.","DOI":"10.3390\/antibiotics9090591"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Paes Leme, R.C., and da Silva, R.B. (2021). Antimicrobial activity of non-steroidal anti-inflammatory drugs on biofilm: Current evidence and potential for drug repurposing. Front. Microbiol., 12.","DOI":"10.3389\/fmicb.2021.707629"},{"key":"ref_15","unstructured":"Ghlichloo, I., and Gerriets, V. (2026, April 23). Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) [Updated 1 May 2023], StatPearls [Internet], Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK547742\/."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3471","DOI":"10.1128\/AAC.01464-06","article-title":"Global challenge of multidrug-resistant Acinetobacter baumannii","volume":"51","author":"Perez","year":"2007","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1016\/S0969-2126(00)00534-7","article-title":"Insights into class D beta-lactamases are revealed by the crystal structure of the OXA10 enzyme from Pseudomonas aeruginosa","volume":"8","author":"Maveyraud","year":"2000","journal-title":"Structure"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"101431","DOI":"10.1016\/j.xcrm.2024.101431","article-title":"The gut microbiome regulates the clinical efficacy of sulfasalazine therapy for IBD-associated spondyloarthritis","volume":"5","author":"Lima","year":"2024","journal-title":"Cell Rep. Med."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"AlQumaizi, K.I., Kumar, S., Anwer, R., and Mustafa, S. (2022). Differential Gene Expression of Efflux Pumps and Porins in Clinical Isolates of MDR Acinetobacter baumannii. Life, 12.","DOI":"10.3390\/life12030419"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/s13756-017-0180-5","article-title":"Co-existence of blaOXA-23 and blaNDM-1 genes of Acinetobacter baumannii isolated from Nepal: Antimicrobial resistance and clinical significance","volume":"6","author":"Joshi","year":"2017","journal-title":"Antimicrob. Resist. Infect. Control"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"143665","DOI":"10.1016\/j.ijbiomac.2025.143665","article-title":"Multimodal evaluation of lipoxygenase-targeting NSAIDs using integrated in vitro, SAR, in silico, cytotoxicity towards MCF-7 cell line, DNA docking and MD simulation approaches","volume":"314","author":"Iqbal","year":"2025","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Zahra, N., Zeshan, B., and Ishaq, M. (2022). Carbapenem resistance gene crisis in A. baumannii: A computational analysis. BMC Microbiol., 22.","DOI":"10.1186\/s12866-022-02706-8"},{"key":"ref_23","unstructured":"Choi, J., Patel, P., and Fenando, A. (2026, April 23). Sulfasalazine [Updated 21 March 2024], StatPearls [Internet], Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK557809\/."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6390\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T09:35:48Z","timestamp":1784540148000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6390"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,18]]},"references-count":23,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27146390"],"URL":"https:\/\/doi.org\/10.3390\/ijms27146390","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,18]]}}}